WO2019197466A1 - Method for cleavage of solid phase-bound peptides from the solid phase - Google Patents

Method for cleavage of solid phase-bound peptides from the solid phase Download PDF

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Publication number
WO2019197466A1
WO2019197466A1 PCT/EP2019/059083 EP2019059083W WO2019197466A1 WO 2019197466 A1 WO2019197466 A1 WO 2019197466A1 EP 2019059083 W EP2019059083 W EP 2019059083W WO 2019197466 A1 WO2019197466 A1 WO 2019197466A1
Authority
WO
WIPO (PCT)
Prior art keywords
capping
solid phase
cleavage
fmoc
polypeptide
Prior art date
Application number
PCT/EP2019/059083
Other languages
English (en)
French (fr)
Inventor
Wolfgang Fiedler
Norbert PLEUSS
Bernd Henkel
Manfred Gerken
Original Assignee
Sanofi-Aventis Deutschland Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi-Aventis Deutschland Gmbh filed Critical Sanofi-Aventis Deutschland Gmbh
Priority to AU2019250359A priority Critical patent/AU2019250359A1/en
Priority to KR1020207032152A priority patent/KR20200142033A/ko
Priority to SG11202010017SA priority patent/SG11202010017SA/en
Priority to BR112020020652-0A priority patent/BR112020020652A2/pt
Priority to MX2020010716A priority patent/MX2020010716A/es
Priority to CA3096493A priority patent/CA3096493A1/en
Priority to JP2020555353A priority patent/JP7434169B2/ja
Priority to EP19716166.4A priority patent/EP3774837A1/en
Priority to CN201980037160.4A priority patent/CN112543763A/zh
Publication of WO2019197466A1 publication Critical patent/WO2019197466A1/en
Priority to IL277838A priority patent/IL277838A/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/12—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by hydrolysis, i.e. solvolysis in general
    • C07K1/122—Hydrolysis with acids different from HF
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/042—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers characterised by the nature of the carrier
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/10—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using coupling agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57563—Vasoactive intestinal peptide [VIP]; Related peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons

Definitions

  • in small amounts means in particular that additional compounds, such as impurities of the trifluoroacetic acid or/and 1 ,2-ethanedithiol, can be present in the composition of the invention or in the reaction mixture used in the method of the invention, in an amount of up to 1 % v/v, up to 0.5% v/v, up to 0.2% v/v, up to 0.1 % v/v, up to 0.05% v/v, or up to 0.02% v/v. If impurities are present which can be solids, the percentage is expressed as w/v.
  • the amino acid building block according to the invention can comprise artificial amino acids such as Met(O) (methionine sulfoxide or methionine sulfone), Trp(0 2 ) (N-formylkynurenine) and/or isoAsp (b- aspartate or isoaspartate).
  • the amino acids are selected from Ser, Thr, Trp, Lys, Ala, Asn, Asp, Val, Met, Phe, lie, Pro, Arg, Glu, Gin, Leu, in particular each in the D-form or each in the L-form, and Gly.
  • the amino acid building block according to the invention comprises amino acids selected from Arg, Glu, Gin, Leu, in particular each in the D-form or each in the L-form, and Gly.
  • At least one side chain of the amino acid building block according to the invention can be protected by a further protective group.
  • the further protective group is preferably orthogonal to the N-terminal protective group.
  • Suitable protective groups for said side chains are known by the person skilled in the art. Examples for suitable protective groups are e.g. Trt, Boc, Bzl, PDF, tBu and OtBu, which can be used for the protection of specific side chains. The person skilled in the art is aware of which side chain needs to be protected by which kind of protective group.
  • amino acid building blocks as mentioned in Example 1.4 can be used. In case the amino acid building block comprises more than one side chain, one or more of these side chains can be protected by protective groups, independently selected from suitable protective groups as known by the person skilled in the art.
  • Analogues and derivatives of exendin-3 and/or exendin-4 particularly comprise a modified amino acid sequence.
  • the amino acid sequence is modified by deletion of one or more amino acids (e.g. desPro 36 , desPro 37 , desAsp 28 , desMet(0 14 ) in exendin-4 and the respective positions in exendin-3).
  • one or more amino acids can be replaced (e.g. Met(0 14 ), Trp(0 2 ) 25 , isoAsp 28 , Asp 28 , Pro 38 in exendin-4 and the respective positions in exendin-3), wherein naturally occurring or artificial amino acids such as e.g.
  • H-(Lys) 6 -desPro 36 [Met(0) 14 , Trp(0 2 ) 25 ,Asp 28 ]exendin-4(1-39)-Lys 6 -NH 2 , desAsp 28 Pro 36 , Pro 37 , Pro 38 [Met(0) 14 , Trp(0 2 ) 25 ]exendin-4(1-39)-NH 2 , H-(Lys) 6 -desPro 36 , Pro 37 , Pro 38 [Met(0) 14 , Trp(0 2 ) 25 ,Asp 28 ]exendin-4(1-39)- NH 2 ,
  • the peptide to be synthesized can be a peptide as described herein.
  • the polypeptide can selected from GLP-1 , analogs and derivatives thereof, exendin-3, analogs and derivatives thereof, and exendin-4, analogs and derivatives thereof, as described herein.
  • the polypeptide is selected from exendin-4 and lixisenatide.
  • a preferred polypeptide is lixisenatide.
  • the polypeptide can also be selected from alblglutide, dulaglutide and semaglutide.
  • the polypeptide to be synthesized is preferably lixisenatide or exendin-4, wherein, after coupling of the amino acid building block Arg(20), Glu (17), Gln(13), Leu(10) or/and Gly(4), a capping step can be performed between steps (c) and (d).
  • capping is the acetylation of a free, unprotected N-terminal amino group to which no amino acid building block has been coupled, in order to terminate chain elongation in these molecules. Such capped molecules can be removed from the product during purification. Capping is described in Figure 1.
  • Figure 6 Comparison of the synthesis of lixisenatide using the method of capping according to the invention (B) in comparison to capping with 10% acetic anhydride and 5% v/v DIPEA in DMF for 20 min (A) by means of HPLC chromatography. (C) overlap of HPLC chromatograms of (A) and (B).
  • Figure 15 Ac(8-44) formation, depending upon the capping cocktail and temperature.
  • Figure 17 Comparison of Ac(X-44) content in capping at 9 different positions in the lixisenatide synthesis at 15 °C, room temperature (RT) and 30 °C.
  • the coupling of the first Fmoc-amino acid, Fmoc-Lys(Boc)-OFI was carried out in an excess of 2.4 eq, in order to load the resin.
  • HOBt hydrate, HBTU and DIPEA served as coupling reagents.
  • the coupling time was 60-120 min.
  • the reactor was filled with 26.3 I of DMF. At the same time, 1.2 I of DMF, 0.53 I of acetic anhydride and 0.26 I of diisopropylethylamine (DIPEA) were mixed in a 2 I Schott bottle and added to the resin in the reactor. The reactor was stirred for 10 minutes, then filtering with suction was carried out. After the capping, the resin was washed 5 times in the following sequence: DMF (24 I), isopropanol (31.1 I), DMF (8 I), DMF (31.5 I), DMF (31.5 I). The reactor here was filled each time with the respective washing solvent, then stirring was carried out for 3 minutes and filtering with suction was carried out again.
  • DIPEA diisopropylethylamine
  • GMP capping compound20 min, 10 % Ac20, 5 % DIPEA“ can be performed at different positions between 15°C and room temperature, which can be 20-23°C.
  • Figure 18 shows a comparison of GMP capping of Ac[(X-1 )-44], depending on reaction temperature. Values given for 15 °C and 30 °C are positive and negative deviations from "room temperature” values (grey area)

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Endocrinology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Vascular Medicine (AREA)
  • Peptides Or Proteins (AREA)
PCT/EP2019/059083 2018-04-10 2019-04-10 Method for cleavage of solid phase-bound peptides from the solid phase WO2019197466A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
AU2019250359A AU2019250359A1 (en) 2018-04-10 2019-04-10 Method for cleavage of solid phase-bound peptides from the solid phase
KR1020207032152A KR20200142033A (ko) 2018-04-10 2019-04-10 고체상으로부터 고체상-결합된 펩타이드를 절단하는 방법
SG11202010017SA SG11202010017SA (en) 2018-04-10 2019-04-10 Method for cleavage of solid phase-bound peptides from the solid phase
BR112020020652-0A BR112020020652A2 (pt) 2018-04-10 2019-04-10 método para clivagem de peptídeos ligados à fase sólida a partir da fase sólida
MX2020010716A MX2020010716A (es) 2018-04-10 2019-04-10 Metodo para escindir de la fase solida peptidos unidos a una fase solida.
CA3096493A CA3096493A1 (en) 2018-04-10 2019-04-10 Method for cleavage of solid phase-bound peptides from the solid phase
JP2020555353A JP7434169B2 (ja) 2018-04-10 2019-04-10 固相からの固相結合ペプチドの切断方法
EP19716166.4A EP3774837A1 (en) 2018-04-10 2019-04-10 Method for cleavage of solid phase-bound peptides from the solid phase
CN201980037160.4A CN112543763A (zh) 2018-04-10 2019-04-10 从固相裂解固相结合肽的方法
IL277838A IL277838A (en) 2018-04-10 2020-10-07 A method for separating a solid-phase bound peptide from the solid phase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP18166546 2018-04-10
EP18166546.4 2018-04-10

Publications (1)

Publication Number Publication Date
WO2019197466A1 true WO2019197466A1 (en) 2019-10-17

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PCT/EP2019/059083 WO2019197466A1 (en) 2018-04-10 2019-04-10 Method for cleavage of solid phase-bound peptides from the solid phase

Country Status (12)

Country Link
US (1) US11560402B2 (ja)
EP (1) EP3774837A1 (ja)
JP (1) JP7434169B2 (ja)
KR (1) KR20200142033A (ja)
CN (1) CN112543763A (ja)
AU (1) AU2019250359A1 (ja)
BR (1) BR112020020652A2 (ja)
CA (1) CA3096493A1 (ja)
IL (1) IL277838A (ja)
MX (1) MX2020010716A (ja)
SG (1) SG11202010017SA (ja)
WO (1) WO2019197466A1 (ja)

Cited By (2)

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CN111116731A (zh) * 2020-01-09 2020-05-08 山东大学 一种基于可溶性疏水标记载体的液相法制备索马鲁肽的方法
CN116332810A (zh) * 2023-03-29 2023-06-27 上海嘉莱多生物技术有限责任公司 一种Fmoc-His(Trt)-Abe-OH的制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112543763A (zh) 2018-04-10 2021-03-23 赛诺菲-安万特德国有限公司 从固相裂解固相结合肽的方法
WO2019197469A1 (en) * 2018-04-10 2019-10-17 Sanofi-Aventis Deutschland Gmbh Lixisenatide synthesis with capping

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111116731A (zh) * 2020-01-09 2020-05-08 山东大学 一种基于可溶性疏水标记载体的液相法制备索马鲁肽的方法
CN116332810A (zh) * 2023-03-29 2023-06-27 上海嘉莱多生物技术有限责任公司 一种Fmoc-His(Trt)-Abe-OH的制备方法
CN116332810B (zh) * 2023-03-29 2023-11-07 上海嘉莱多生物技术有限责任公司 一种Fmoc-His(Trt)-Abe-OH的制备方法

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AU2019250359A1 (en) 2020-11-26
US11560402B2 (en) 2023-01-24
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US20190330266A1 (en) 2019-10-31
BR112020020652A2 (pt) 2021-03-02
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